methyl 3-(4-hydroxyphenyl)-3-oxopropanoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-hydroxyacetophenone (500 g) in DMF (1.5 L) was slowly added to a suspension of sodium hydride (331 g) in DMF. The mixture was stirred for 15 min. till gas evolution had subsided. Dimethyl carbonate (1.55 L) was added and the reaction stirred overnight at room temperature. The reaction was worked up by pouring into ice (15 LB) followed by acidification to pH 2 with hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (3×5 L) and this was washed with water (3×1 L) and brine, then dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography on silica gel (10 Kg) with 15 to 40% ethyl acetate-hexane. The chromatographed product was recrystallized twice from ethyl acetate-hexane to yield 313 gm first crop material as a white powder with mp 90-92° C. the reaction stirred overnight at room temperature by pouring into ice (15 LB) The aqueous mixture was extracted with ethyl acetate (3×5 L) this was washed with water (3×1 L) and brine dried (Na2SO4) filtered concentrated The crude product was purified by chromatography on silica gel (10 Kg) with 15 to 40% ethyl acetate-hexane The chromatographed product was recrystallized twice from ethyl acetate-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 50 mL RB flask fitted with magnetic stirrer was charged 10 mL of Toluene. to the stirred solvent was added methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (0.2 g, 1.036 mmol) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.22 g, 0.82 mmol) was added Tributyl phosphine (0.271 g, 1.324 mmol) and 1,1′-(Azodicarbonyl)di-Piperidine portion wise at 0° C. (0.339 g, 1.346 mmol). Then the reaction mixture was stirred at RT for 12 h. After completion of the reaction (reaction monitored by TLC), reaction mixture was concentrated and extracted with ethyl acetate. Then the organic layer was dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, and the resulting crude compound was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent (0.05 g Yield: 14%) MS (ESI, 120 eV): m/z=448.1 (M+H)+. To a 50 mL RB flask fitted with magnetic stirrer After completion of the reaction (reaction monitored by TLC), reaction mixture was concentrated extracted with ethyl acetate Then the organic layer was dried over anhydrous Na2SO4 Solvent was removed under reduced pressure the resulting crude compound was purified by column chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 50 mL RB flask fitted with magnetic stirrer was charged 10 mL of Toluene. to the stirred solvent was added methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (0.2 g, 1.036 mmol) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.22 g, 0.82 mmol) was added Tributyl phosphine (0.271 g, 1.324 mmol) and 1,1′-(Azodicarbonyl)di-Piperidine portion wise at 0° C. (0.339 g, 1.346 mmol). Then the reaction mixture was stirred at RT for 12 h. After completion of the reaction (reaction monitored by TLC), reaction mixture was concentrated and extracted with ethyl acetate. Then the organic layer was dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, and the resulting crude compound was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent (0.05 g Yield: 14%) MS (ESI, 120 eV): m/z=448.1 (M+H)+. To a 50 mL RB flask fitted with magnetic stirrer After completion of the reaction (reaction monitored by TLC), reaction mixture was concentrated extracted with ethyl acetate Then the organic layer was dried over anhydrous Na2SO4 Solvent was removed under reduced pressure the resulting crude compound was purified by column chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 50 mL RB flask fitted with magnetic stirrer were charged ethyl acetate (15 mL), to that stirred solvent was added methyl 3-[4-(benzyloxy)phenyl]-3-oxopropanoate (0.3 g, 1.05 mmol), and palladium carbon 10% (80 mg) was added. After addition, the hydrogen balloon was fixed to the reaction mixture and stirred at room temperature for 1 h. After 3 h, the reaction mixture was filtered through celite. Then the organic layer was concentrated and dried. The product was obtained as colourless liquid (0.2 g, Yield: 98%). To a 50 mL RB flask fitted with magnetic stirrer was added After addition stirred at room temperature for 1 h the reaction mixture was filtered through celite Then the organic layer was concentrated dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL RB flask fitted with magnetic stirrer was charged with sodium hydride (3.5 g, 147 mmol). At 0 deg C., 100 mL of DMF was added slowly with stirring. To the stirred solvent were added 1-(4-hydroxyphenyl)ethanone (5 g, 36 mmol) and dimethylcarbonate (15.5 g, 170 mmol), stirred at room temperature overnight. The RM was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as elutants. The product was obtained as pale yellow oil (3.4 g, yield: 47.66%). MS (ESI, 120 eV): m/z=195 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.79-7.82 (d, 2H), 6.81-6.84 (d, 2H), 6.21 (br s, 1H), 3.90 (s, 2H), 3.69 (s, 3H). To a 250 mL RB flask fitted with magnetic stirrer At 0 deg C stirred at room temperature overnight extracted with ethyl acetate (100 mL) The organic layer was washed with water (50 mL) and saturated brine solution (50 mL) The organic layer was dried over anhydrous Na2SO4 the solvent was removed under reduced pressure The crude material was purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL RB flask fitted with magnetic stirrer was charged with sodium hydride (3.5 g, 147 mmol). At 0 deg C., 100 mL of DMF was added slowly with stirring. To the stirred solvent were added 1-(4-hydroxyphenyl)ethanone (5 g, 36 mmol) and dimethylcarbonate (15.5 g, 170 mmol), stirred at room temperature overnight. The RM was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as elutants. The product was obtained as pale yellow oil (3.4 g, yield: 47.66%). MS (ESI, 120 eV): m/z=195 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.79-7.82 (d, 2H), 6.81-6.84 (d, 2H), 6.21 (br s, 1H), 3.90 (s, 2H), 3.69 (s, 3H). To a 250 mL RB flask fitted with magnetic stirrer At 0 deg C stirred at room temperature overnight extracted with ethyl acetate (100 mL) The organic layer was washed with water (50 mL) and saturated brine solution (50 mL) The organic layer was dried over anhydrous Na2SO4 the solvent was removed under reduced pressure The crude material was purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-hydroxyacetophenone (500 g) in DMF (1.5 L) was slowly added to a suspension of sodium hydride (331 g) in DMF. The mixture was stirred for 15 min. till gas evolution had subsided. Dimethyl carbonate (1.55 L) was added and the reaction stirred overnight at room temperature. The reaction was worked up by pouring into ice (15 LB) followed by acidification to pH 2 with hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (3×5 L) and this was washed with water (3×1 L) and brine, then dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography on silica gel (10 Kg) with 15 to 40% ethyl acetate-hexane. The chromatographed product was recrystallized twice from ethyl acetate-hexane to yield 313 gm first crop material as a white powder with mp 90-92° C. the reaction stirred overnight at room temperature by pouring into ice (15 LB) The aqueous mixture was extracted with ethyl acetate (3×5 L) this was washed with water (3×1 L) and brine dried (Na2SO4) filtered concentrated The crude product was purified by chromatography on silica gel (10 Kg) with 15 to 40% ethyl acetate-hexane The chromatographed product was recrystallized twice from ethyl acetate-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-hydroxyacetophenone (500 g) in DMF (1.5 L) was slowly added to a suspension of sodium hydride (331 g) in DMF. The mixture was stirred for 15 min. till gas evolution had subsided. Dimethyl carbonate (1.55 L) was added and the reaction stirred overnight at room temperature. The reaction was worked up by pouring into ice (15 LB) followed by acidification to pH 2 with hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (3×5 L) and this was washed with water (3×1 L) and brine, then dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography on silica gel (10 Kg) with 15 to 40% ethyl acetate-hexane. The chromatographed product was recrystallized twice from ethyl acetate-hexane to yield 313 gm first crop material as a white powder with mp 90-92° C. the reaction stirred overnight at room temperature by pouring into ice (15 LB) The aqueous mixture was extracted with ethyl acetate (3×5 L) this was washed with water (3×1 L) and brine dried (Na2SO4) filtered concentrated The crude product was purified by chromatography on silica gel (10 Kg) with 15 to 40% ethyl acetate-hexane The chromatographed product was recrystallized twice from ethyl acetate-hexane

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (1 g) and EtONH2.HCl (600 mg) in methanol (10 mL) was heated at 65° C. for 2 h. Methanol was removed in vacuo, and saturated sodium bicarbonate was added to the residue. The aqueous solution was extracted with ethyl acetate (×4), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as a colorless oil, which was used directly in Step B. HPLC retention time: 1.51 min (method A). MS (ESI) (M+H)+ 238.09. Methanol was removed in vacuo, and saturated sodium bicarbonate was added to the residue The aqueous solution was extracted with ethyl acetate (×4) the combined organic layers were washed with brine dried over anhydrous sodium sulfate filtered The filtrate was evaporated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (7.8 g, 40.2 mmol) and 4,4,4-trifluorobutan-1-ol (5.15 g, 40.2 mmol) in CH2Cl2 (201 mL) at 0° C. was added triphenylphosphine (12.6 g, 48.2 mmol). The mixture was stirred for a few min, and then DIAD (9.37 mL, 48.2 mmol) was added. The reaction was stirred at 0° C. for 30 min, then warmed to rt and stirred for 3 days. The reaction was loaded directly onto a 300 g silica gel column and eluted with EtOAc in hexanes. Fractions containing the product were combined and concentrated to provide Intermediate 14A (9.9 g, 80%) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 2.03-2.13 (m, 2H), 2.26-2.39 (m, 2H), 3.75 (s, 3H), 3.96 (s, 2H), 4.09 (t, J=6.05 Hz, 2H), 6.92-6.96 (m, 2H), 7.86-7.97 (m, 2H). The reaction was stirred at 0° C. for 30 min stirred for 3 days eluted with EtOAc in hexanes Fractions containing the product concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 50 mL RB flask fitted with magnetic stirrer was charged 10 mL of Toluene. to the stirred solvent was added methyl 3-(4-hydroxyphenyl)-3-oxopropanoate (0.2 g, 1.036 mmol) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.22 g, 0.82 mmol) was added Tributyl phosphine (0.271 g, 1.324 mmol) and 1,1′-(Azodicarbonyl)di-Piperidine portion wise at 0° C. (0.339 g, 1.346 mmol). Then the reaction mixture was stirred at RT for 12 h. After completion of the reaction (reaction monitored by TLC), reaction mixture was concentrated and extracted with ethyl acetate. Then the organic layer was dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, and the resulting crude compound was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent (0.05 g Yield: 14%) MS (ESI, 120 eV): m/z=448.1 (M+H)+. To a 50 mL RB flask fitted with magnetic stirrer After completion of the reaction (reaction monitored by TLC), reaction mixture was concentrated extracted with ethyl acetate Then the organic layer was dried over anhydrous Na2SO4 Solvent was removed under reduced pressure the resulting crude compound was purified by column chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 50 mL RB flask fitted with magnetic stirrer were charged ethyl acetate (15 mL), to that stirred solvent was added methyl 3-[4-(benzyloxy)phenyl]-3-oxopropanoate (0.3 g, 1.05 mmol), and palladium carbon 10% (80 mg) was added. After addition, the hydrogen balloon was fixed to the reaction mixture and stirred at room temperature for 1 h. After 3 h, the reaction mixture was filtered through celite. Then the organic layer was concentrated and dried. The product was obtained as colourless liquid (0.2 g, Yield: 98%). To a 50 mL RB flask fitted with magnetic stirrer was added After addition stirred at room temperature for 1 h the reaction mixture was filtered through celite Then the organic layer was concentrated dried